Amino-thio-acrylonitriles as MEK inhibitors

ABSTRACT

This invention relates generally to amino-thio-acrylonitriles of formula Ia or Ib:  
                 
 
     as MEK inhibitors, pharmaceutical compositions containing the same, and methods of using the same as for treatment and prevention of inflammatory disorders or as an anticancer radiosensitizing agent.

FIELD OF THE INVENTION

[0001] This invention relates generally to amino-thio-acrylonitriles asMEK inhibitors, pharmaceutical compositions containing the same, andmethods of using the same as for treatment and prevention ofinflammatory disorders, cancer or other proliferative diseases or as aradiosensitizing agents against cancer or other proliferative disorders.

BACKGROUND OF THE INVENTION

[0002] The mitogen activated protein kinase (MAPK) signaling pathwaysare involved in cellular events such as growth, differentiation andstress responses (J. Biol. Chem. (1993) 268, 14553-14556). Four parallelpathways have been identified to date ERK1/ERK2, JNK, p38 and ERK5.These pathways are linear kinase cascades in that MAPKKK phosphorylatesand activates MAPKK that phosphorylates and activates MAPK. To date,there are 7 MAPKK homologs (MEK1, MEK2, MKK3, MKK4/SEK, MEK5, MKK6, andMKK7) and 4 MAPK families (ERK1/2, JNK, p38, and ERK5). The MAPKK familymembers are unique in that they are dual-specific kinases,phosphorylating MAPKs on threonine and tyrosine. Activation of thesepathways regulates the activity of a number of substrates throughphosphorylation. These substrates include transcription factors such asTCF, c-myc, ATF2 and the AP-1 components, fos and Jun; the cell surfacecomponents EGF-R; cytosolic components including PHAS-I, p90^(rsk),cPLA₂ and c-Raf-1; and the cytoskeleton components such as tau and MAP2.

[0003] The prototypical mitogen activated protein kinase cascade isreflected by the ERK pathway (Biochem J.(1995) 309, 361-375). The ERKpathway is activated primarily in response to ligation of receptortyrosine kinases (RTKs) (FEBS Lett. (1993) 334, 189-192). Signalpropagation from the RTKs occurs down the Ras pathway through sequentialphosphorylation of Raf, MEK and ERK. This pathway has not been typicallyviewed of as an important contributor to the inflammatory response, butrather involved in growth and differentiation processes. This view stemsfrom the profile of typical activators of this pathway, which includegrowth factors (PDGF, NGF, EGF), mitogens (phorbol esters), andpolypeptide hormones (insulin, IGF-1). Evidence for ERK pathwayinvolvement in inflammatory and immune responses has, however, gainedsome support in recent years (Proc. Natl. Acad. Sci. USA. (1995) 92,1614-1618; J. Immunol. (1995) 155, 1525-1533; and J. Biol. Chem. (1995)270, 27391-27394). Cytokines such as TNFa and IL-1b, the bacterial cellwall mitogen, LPS, and chemotactic factors such as fMLP, C5a, and IL-8all activate the ERK pathway. In addition, the ERK pathway is activatedas a result of T cell receptor ligation with antigen or agents such asPMA/ionomycin or anti-CD3 antibody, which mimic TCR ligation in T cells(Proc. Natl. Acad. Sci. USA (1995) 92, 7686-7689). These findingsindicate that inhibitors of the ERK pathway should function asanti-inflammatory and immune suppressive agents.

[0004] Small molecule inhibitors of the Raf/MEK/ERK pathway have beenidentified. A series of benzoquinones has been disclosed by Parke-Davis,which is exemplified by PD 098059 that inhibits MEK activity (J. Biol.Chem. (1995) 46, 27498-27494). Recently, we identified a MEK inhibitor,U0126 (J. Biol. Chem. (1998) 29, 18623-18632). Comparative kineticanalysis showed that U0126 and PD 098059 were non-competitive inhibitorsof activated MEK (J. Biol. Chem. (1998) 29, 18623-18632). These MEKinhibitors have been used to investigate the role of the ERK activationcascade in a wide variety of systems including inflammation, immunesuppression and cancer. For example, PD 098059 blocks thymidineincorporation into DNA in PDGF-stimulated Swiss 3T3 cells (J. Biol.Chem. (1995) 46, 27498-27494). PD 098059 also prevents PDGF-BB-dependentSMC (Smooth Muscle Cell) chemotaxis at concentrations which inhibit ERKactivation (Hypertension (1997) 29, 334-339). Similarly, U0126 preventsPDGF-dependent growth of serum starved SMC. We have also shown thatU0126 blocks keratinocyte proliferation in response to a pituitarygrowth factor extract, which consists primarily of FGF. These datacoupled with those obtained with PD 098059 above indicate that MEKactivity is essential for growth factor-stimulated proliferation.

[0005] The role of the MEK/ERK pathway in inflammation and immunesuppression has been examined in a number of systems, including modelsof T cell activation. The T cell antigen receptor (TCR) is a non-RTKreceptor whose intracellular signaling pathways have been elucidated (6iProc. Natl. Acad. Sci. USA (1995) 92, 7686-7689). DeSilva et al. havegenerated a great deal of information with U0126 in T cell systems (J.Immunol. (1998) 160, 4175-4181). Their data showed that U0126 preventsERK activation in T cells in response to PMA/ionomycin, Con Astimulation, and antigen in the presence of costimulation. In addition,T cell activation and proliferation in response TCR engagement isblocked by U0126 as is IL-2 synthesis. These results indicate that MEKinhibition does not result in a general antiproliferative effect in thisIL-2-driven system, but selectively blocks components of the signalingcascades initiated by T cell receptor engagement.

[0006] PD 098059 has also been shown to inhibit T cell proliferation inresponse to anti-CD3 antibody, which is reversed by IL-2-(J. Immunol.(1998)- 160, 2579-2589.). PD 098059 also blocked IL-2 production by Tcells stimulated with anti-CD3 antibody in combination with eitheranti-CD28 or PMA. In addition, the MEK inhibitor blocked TNFa, IL-3GM-CSF, IFN-g, IL-6 and IL-10 production. In contrast, PD 098059enhanced production of IL-4, IL-5 and IL-13 in similarly stimulated Tcell cultures. These differential T cells effects with MEK inhibitionsuggest that therapeutic manipulations may be possible.

[0007] Neutrophils show ERK activation in response to the agonistsN-formyl peptide (fMLP), IL-8, CSa and LTB₄, which is blocked by PD098059 (Biochem. Biophy. Res. Commun. (1997) 232, 474-477).Additionally, PD 098059 blocks neutrophil chemotaxis in response to allagents, but does not alter superoxide anion production. However,fMLP-stimulated superoxide generation was inhibited by PD098059 in HL-60cells (J. Immunol. (1997) 159, 5070-5078), suggesting that this effectmay be cell-type specific. U0126 blocks ERK activation in fMLP- andLTB₄-stimulated neutrophils, but does not impair NADPH-oxidase activityor bacterial cell killing. U0126 at 10 mM blunts up regulation of b2integrin on the cell surface by 50% and blocks chemotaxis through afibrin gel >80% in response to IL-8 and LTB₄. Thus, neutrophil mobilityis affected by MEK inhibition although the acute functional responses ofthe cell remain intact.

[0008] Eicosanoids are key mediators of the inflammatory response. Theproximal event leading to prostaglandin and leukotriene biosynthesis isarachidonic acid release from membrane stores, which is mediated largelythrough the action of cytosolic phospholipase A₂ (cPLA₂). Activation ofcPLA₂ requires Ca²⁺ along with phosphorylation on a consensus MAP kinasesite, Ser505, which increases catalytic efficiency of the enzyme (J.Biol. Chem. (1997) 272, 16709-16712). In neutrophils, mast cells, orendothelial cells, PD 098059 blocks arachidonic acid release in responseto opsonized zymosan, aggregation of the high affinity IgG receptor, orthrombin, respectively. Such data support a role for ERK as the mediatorof cPLA₂ activation through phosphorylation (FEBS Lett. (1996) 388,180-184. Biochem J. (1997) 326, 867-876 and J. Biol. Chem. (1997) 272,13397-13402). Similarly, U0126 is able to block arachidonic acid releasealong with prostaglandin and leukotriene synthesis in keratinocytesstimulated with a variety of agents. Thus, the effector target, cPLA₂,is sensitive to MEK inhibition in a variety of cell types.

[0009] MEK inhibitors also seem to affect eicosanoid production throughmeans other than inhibition of arachidonic acid release. PD 098059partially blocked LPS-induced Cox-2 expression in RAW 264.7 cells,indicating ERK activation alone may not be sufficient to induceexpression of this key enzyme mediating inflammatory prostanoidproduction (Biochem J. (1998) 330, 1107-1114). Similarly, U0126 inhibitsCox-2 induction in TPA-stimulated fibroblasts, although it does notimpede serum induction of the Cox-2 transcript. PD 098059 also inhibitsCox-2 induction in lysophosphatidic acid (LPA)-stimulated rat mesangialcells, which further supports a role for ERK activation in production ofprostaglandins (Biochem J. (1998) 330, 1107-1114). Finally,5-lipoxygenase translocation from the cytosol to the nuclear membranealong with its activation as measured by 5-HETE production can beinhibited by PD 098059 in HL-60 cells (Arch. Biochem. Biophys. (1996)331, 141-144).

[0010] Inflammatory cytokines such as TNFa and IL-1b are criticalcomponents of the inflammatory response. Cytokine production in responseto cell activation by various stimuli as well as their activation ofdownstream signaling cascades represent novel targets for therapeutics.Although the primary effect of IL-1b and TNF-a is to up regulate thestress pathways (Nature (1994) 372, 729-746), published reports (Proc.Natl. Acad. Sci. USA (1995) 92, 1614-1618. J. Immunol. (1995) 155,1525-1533. J. Biol. Chem. (1995) 270, 27391-27394. Eur. J.). Cytokinessuch as TNFa and IL-1b, the bacterial cell wall mitogen, LPS, andchemotactic factors such as fMLP, C5a, and IL-8 all activate the ERKpathway. In addition, the ERK pathway is activated as a result of T cellreceptor ligation with antigen or agents such as PMA/ionomycin oranti-CD3 antibody, which mimic TCR ligation in T cells (Proc. Natl.Acad. Sci. USA (1995) 92, 7686-7689) and clearly show that the ERKpathway is also affected. U0126 can block MMP induction by IL-1b andTNF-a in fibroblasts (J. Biol. Chem. (1998) 29, 18623-18632),demonstrating that ERK activation is necessary for this proinflammatoryfunction. Similarly, lipopolysaccharide (LPS) treatment of monocytesresults in cytokine production that has been shown to be MAPkinase-dependent being blocked by PD 098059 (J. Immunnol. (1998) 160,920-928). Indeed, we have observed similar results in freshly isolatedhuman monocytes and THP-1 cells where LPS-induced cytokine production isinhibitable by U0126 (J. Immunol. (1998) 161:5681-5686).

[0011] The proximal involvement of RAS in the activation of the ERKpathway suggests that MEK inhibition might show efficacy in models whereoncogenic RAS is a determinant in the cancer phenotype. Indeed, PD098059 (J. Biol. Chem. (1995) 46, 27498-27494) as well as U0126 are ableto impede the growth of RAS-transformed cells in soft agar even thoughthese compounds show minimal effects on cell growth under normal cultureconditions. We have further examined the effects of U0126 on the growthof human tumor cell lines in soft agar. We have shown that U0126 canprevent cell growth in some cells, but not all, suggesting that a MEKinhibitor may be effective in only certain kinds of cancer. In addition,PD 098059 has been shown to reduce urokinase secretion controlled bygrowth factors such as EGF, TGFa and FGF in an autocrine fashion in thesquamous cell carcinoma cell lines UM-SCC-1 and MDA-TV-138 (Cancer Res.(1996) 56, 5369-5374). In vitro invasiveness of UM-SCC-1 cells throughan extracellular matrix-coated porous filter was blocked by PD 098059although cellular proliferation rate was not affected. These resultsindicate that control of the tumor invasive phenotype by MEK inhibitionmay also be a possibility. The observed effects with PD 098059 and U0126suggest that MEK inhibition may have potential for efficacy in a numberof disease states. Our own data argue strongly for the use of MEKinhibitors in T-cell mediated diseases where immune suppression would beof value. Prevention of organ transplant rejection, graft versus hostdisease, lupus erythematosus, multiple sclerosis, and rheumatoidarthritis are potential disease targets. Effects in acute and chronicinflammatory conditions are supported by the results in neutrophils andmacrophage systems where MEK inhibition blocks cell migration andliberation of proinflammatory cytokines. A use in conditions whereneutrophil influx drives tissue destruction such as reperfusion injuryin myocardial infarction and stroke as well as inflammatory arthritismay be warranted. Blunting of SMC migration and inhibition of DNAreplication would suggest atherosclerosis along with restenosisfollowing angioplasty as disease indications for MEK inhibitors. Skindisease such as psoriasis provides another potential area where MEKinhibitors may prove useful since MEK inhibition prevents skin edema inmice in response to TPA. MEK inhibition also blocks keratinocyteresponses to growth factor cocktails, which are known mediators in thepsoriatic process.

[0012] Finally, the use of a MEK inhibitor in cancer can not beoverlooked. Ionizing radiation initiates a process of apoptosis or celldeath that is useful in the treatment solid tumors. This processinvolves a balance between pro-apoptotic and anti-apoptotic signal(Science 239, 645-647), which include activation of MAP kinase cascades.Activation of the SAPK pathway delivers a pro-apoptotic signal(Radiotherapy and Oncology (1998) 47, 225-232.), whereas activation ofthe MAPK pathway is anti-apoptotic (Nature (1996) 328, 813-816.).Interference with the anti-apoptotic MAPK pathway by dominant negativeMEK2 or through direct inhibition of MEK with synthetic inhibitorssensitizes cells to radiation-induced cell death (J. Biol. Chem. (1999)274, 2732-2742; and Oncogene (1998) 16, 2787-2796).

[0013] WO98/37881 describe MEK inhibitors useful for treating orpreventing septic shock. The inhibitors include2-(2-amino-3-methoxyphenyl)-4-oxo-4H[1]benzopyran and a compound of theformula:

[0014] The above diphenyl amines are not considered to be part of thepresently claimed invention.

[0015] Therefore, efficacious and specific MEK inhibitors are needed aspotentially valuable therapeutic agents for the treatment ofinflammatory disorders, cancer or other proliferative diseases or as aradiosensitizing agents against cancer or other proliferative disorders.It is thus desirable to discover new MEK inhibitors.

SUMMARY OF THE INVENTION

[0016] Accordingly, one object of the present invention is to providenovel amino-thio-acrylonitriles which are useful as MEK inhibitors orpharmaceutically acceptable salts or prodrugs thereof.

[0017] It is another object of the present invention to providepharmaceutical compositions comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltor prodrug form thereof.

[0018] It is another object of the present invention to provide a methodfor treating a disorder involving MEK, comprising: administering to ahost in need of such treatment a therapeutically effective amount of atleast one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

[0019] It is another object of the present invention to provide a novelmethod of using the compounds of the present invention as aradiosensitizing agent for the treatment of cancers or proliferativediseases, comprising: administering to a host in need of such treatmenta therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable prodrug or salt formthereof.

[0020] It is another object of the present invention to provide a novelmethod of treating a condition or disease wherein the disease orcondition is referred to as rheumatoid arthritis, osteoarthritis,periodontitis, gingivitis, corneal ulceration, solid tumor growth andtumor invasion by secondary metastases, neovascular glaucoma, multiplesclerosis, or psoriasis in a mammal, comprising: administering to themammal in need of such treatment a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt formthereof.

[0021] It is another object of the present invention to provide a novelmethod of treating a condition or disease wherein the disease orcondition is referred to as fever, cardiovascular effects, hemorrhage,coagulation, cachexia, anorexia, alcoholism, acute phase response, acuteinfection, shock, graft versus host reaction, autoimmune disease or HIVinfection in a mammal comprising administering to the mammal in need ofsuch treatment a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt form thereof.

[0022] It is another object of the present invention to provide novelamino-thio-acrylonitriles or salts or prodrugs thereof for use intherapy.

[0023] It is another object of the present invention to provide the useof novel amino-thio-acrylonitriles or salts or prodrugs thereof for themanufacture of a medicament for the treatment of an inflammatorydisease.

[0024] It is another object of the present invention to provide the useof novel amino-thio-acrylonitriles or salts or prodrugs thereof for themanufacture of a medicament for the treatment of cancer.

[0025] These and other objects, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that compounds of formula Ia or Ib:

[0026] or pharmaceutically acceptable salt or prodrug forms thereof,wherein R¹ and R² are defined below, are effective MEK inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0027] Thus, in a first embodiment, the present invention provides anovel compound of formula Ia or Ib:

[0028] or stereoisomer or pharmaceutically acceptable salt form thereof,wherein;

[0029] R¹ is phenyl, naphthyl, 2,3-dihydroindol-5-yl or a 5-6 memberedheteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, andR¹ is substituted with 0-2 R^(a); R^(a) is selected from H, Cl, F, Br,I, C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, CH_(2O)OH, NH₂, (C₁₋₃ alkyl)NH, (C₁₋₃alkyl)₂N, (H₂NCH₂C(O))NH, (H₂NCH(CH₃)C(O))NH, (CH₃NHCH₂C(O))NH,((CH₃)₂NCH₂C(O))NH, CF₃, OCF₃, —CN, NO₂, C(O)NH₂, and CH₃C(O)NH;

[0030] Y is selected from phenyl substituted with 0-5 R^(b), naphthylsubstituted with 0-5 R^(b), and CHR³;

[0031] Rb is selected from H, Cl, F, Br, I, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,CH₂OH, CH(OH)CH₃, CF₃, OCF₃, —CN, NO₂, NH₂, (C₁₋₃ alkyl)NH, (C₁₋₃alkyl)₂N, and C(O)O—C₁₋₄ alkoxy;

[0032] R² is selected from H, R^(2a), C(O)R^(2a), CH(OH)R^(2a),CH₂R^(2a), OR^(2a), SR^(2a), and NHR^(2a);

[0033] R^(2a) is selected from phenyl, naphthyl, and a 5-6 memberedheteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, andR^(2a) is substituted with 0-5 R^(b);

[0034] R³ is phenyl substituted with 0-2 R^(c) or naphthyl substitutedwith 0-2 R^(c); and,

[0035] R^(c) is selected from H, Cl, F, Br, I, C₁₋₄ alkyl, OH, C₁₋₄alkoxy, CH₂OH, CH(OH)CH₃, CF₃, OCF₃, —CN, NO₂, NH₂, (C₁₋₃ alkyl)NH,(C₁₋₃ alkyl)₂N, and C(O)O—C₁₋₄ aIkoxy.

[0036] In a preferred embodiment, the present invention provides a novelcompound, wherein: R¹ is phenyl or a 5-6 membered heteroaryl ring with1-2 heteroatoms selected from N, NH, O, and S, and R¹ is substitutedwith 0-2 R^(a);

[0037] Ra is selected from H, Cl, F, C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, CH₂OH,NH₂, (C₁₋₃ alkyl)NH, (C₁₋₃ alkyl)₂N, (H₂NCH₂C(O))NH, (H₂NCH(CH₃)C(O))NH,(CH₃NHCH₂C(O))NH, ((CH₃)₂NCH₂C(O))NH, and CH₃C(O)NH;

[0038] Y is selected from phenyl substituted with 0-5 R^(b), naphthylsubstituted with 0-5 R^(b), and CHR³;

[0039] R^(b) is selected from H, Cl, F, Br, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,CH₂OH, CH(OH)CH₃, CF₃, —CN, NO₂, NH₂, and (C₁₋₃ alkyl)NH, (C₁₋₃alkyl)₂N;

[0040] R² is selected from H, R^(2a), C(O)R^(2a), CH(OH)R^(2a),CH₂R^(2a), and OR^(2a);

[0041] R^(2a) is selected from phenyl, naphthyl, and a 5-6 memberedheteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, andR^(2a) is substituted with 0-5 R^(b);

[0042] R³ is phenyl substituted with 0-2 R^(c) or naphthyl substitutedwith 0-2 R^(c); and,

[0043] R^(c) is selected from H, Cl, F, Br, I, C₁₋₄ alkyl, OH, C₁₋₄alkoxy, CH₂OH, CH(OH)CH₃, CF₃, —CN, NO₂, NH₂, (C₁₋₃ alkyl)NH, and (C₁₋₃alkyl)₂N.

[0044] In a more preferred embodiment, the present invention provides anovel compound, wherein: R¹ is phenyl or a 5-6 membered heteroaryl ringwith 1-2 heteroatoms selected from N, NH, O, and S, and R¹ issubstituted with 0-2 R^(a);

[0045] Ra is selected from H, OH, and NH₂;

[0046] Y is selected from phenyl substituted with 0-2 R^(b), naphthylsubstituted with 0-2 R^(b), and CHR³;

[0047] R^(b) is selected from H, Cl, F, Br, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,CH₂OH, CH(OH)CH₃, CF₃, —CN, NO₂, NH₂, and (C₁₋₃ alkyl)NH, (C₁₋₃alkyl)₂N;

[0048] R² is selected from H, R^(2a), C(O)R^(2a), CH(OH)R^(2a),CH₂R^(2a), and OR^(2a);

[0049] R^(2a) is selected from phenyl, naphthyl, and a 5-6 memberedheteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, andR^(2a) is substituted with 0-5 R^(b);

[0050] R³ is phenyl substituted with 0-2 R^(c) or naphthyl substitutedwith 0-2 R^(c); and,

[0051] R^(c) is selected from H, Cl, F, Br, I, C₁₋₄ alkyl, OH, C₁₋₄alkoxy, CH₂OH, CH(OH)CH₃, CF₃, —CN, NO₂, NH₂, (C₁₋₃ alkyl)NH, and (C₁₋₃alkyl)₂N.

[0052] In an even more preferred embodiment, the present inventionprovides a novel compound selected from:

[0053] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-β-phenylbenzenepropanenitrile;

[0054] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0055] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile

[0056] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0057] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0058] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzenezcetonitrile,

[0059] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0060] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0061] E- andZ-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0062] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0063] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0064] E- andZ-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0065] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile;

[0066] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0067] E- andZ-α-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0068] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0069] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0070] E- andZ-α-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0071] E- andZ-α-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0072] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;

[0073] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;

[0074] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0075] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;

[0076] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-phenylbenzenepropanenitrile;

[0077] E- andZ-α-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0078] E- andZ-α-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0079] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-β-(4-pyridyl)benzenepropanenitrile;

[0080] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-3-(benzyl)benzeneacetonitrile;

[0081] E- andZ-α-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;

[0082] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;

[0083] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-β-(1-methyl-2-pyrrolyl)benzenepropanenitrile;

[0084] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;

[0085] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;

[0086] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;

[0087] E- andz-α-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0088] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0089] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;

[0090] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;

[0091] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0092] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;

[0093] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0094] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;

[0095] E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;

[0096] E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;

[0097] E- andZ-α-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile;and,

[0098] E- and Z-α-[amino[(2-aminophenyl)thio]methylene]-3-phenylbenzeneacetonitrile; or a pharmaceutically acceptable salt form thereof.

[0099] In a further preferred embodiment, the present invention providesa novel compound selected from:

[0100]E-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-β-phenylbenzenepropanenitrile;

[0101]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0102]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile;

[0103]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0104]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0105]E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0106]E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0107]E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0108]E-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0109]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0110]E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0111]E-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0112]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile;

[0113]E-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0114]E-α-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0115]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0116]E-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0117]E-α-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0118]E-α-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0119]E-α-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;

[0120]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;

[0121]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0122]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;

[0123]E-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-phenylbenzenepropanenitrile;

[0124]E-α-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0125]E-α-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0126]E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-β-(4-pyridyl)benzenepropanenitrile;

[0127]E-α-[amino[(4-aminophenyl)thio]methylene]-3-(benzyl)benzeneacetonitrile;

[0128] E-α-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;

[0129]E-α-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;

[0130]E-α-[amino[(2-aminophenyl)thio]methylene]-β-(1-methyl-2-pyrrolyl)benzenepropanenitrile;

[0131]E-α-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;

[0132]E-α-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;

[0133]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;

[0134]E-α-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0135]E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0136]E-α-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;

[0137]E-α-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;

[0138]E-α-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0139]E-α-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;

[0140]E-α-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0141]E-α-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;

[0142]E-α-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;

[0143]E-α-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;

[0144]E-α-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile;and,

[0145] E-α-[amino[(2-aminophenyl)thio]methylene]-3-phenylbenzeneacetonitrile; or a pharmaceutically acceptable salt form thereof.

[0146] In a further preferred embodiment, the present invention providesa novel compound selected from:

[0147]Z-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-β-phenylbenzenepropanenitrile;

[0148]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0149]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile

[0150]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0151]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0152]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0153]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0154]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0155]Z-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0156]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;

[0157]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0158]Z-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0159]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile;

[0160]Z-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0161]Z-α-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0162]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0163]Z-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0164]Z-α-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;

[0165]Z-α-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0166]Z-α-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;

[0167]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;

[0168]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0169]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;

[0170]Z-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-phenylbenzenepropanenitrile;

[0171]Z-α-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;

[0172]Z-α-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0173]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-β-(4-pyridyl)benzenepropanenitrile;

[0174]Z-α-[amino[(4-aminophenyl)thio]methylene]3-(benzyl)benzeneacetonitrile;

[0175] Z-α-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;

[0176]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;

[0177]Z-α-[amino[(2-aminophenyl)thio]methylene]-β-(1-methyl-2-pyrrolyl)benzenepropanenitrile;

[0178]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;

[0179]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;

[0180]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;

[0181]Z-α-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;

[0182]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;

[0183]Z-α-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;

[0184]Z-α-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;

[0185]Z-α-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;.

[0186]Z-α-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;

[0187]Z-α-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;

[0188]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;

[0189]Z-α-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;

[0190]Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;

[0191]Z-α-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile;and,

[0192] Z-α-[amino[(2-aminophenyl)thio]methylene]-3-phenylbenzeneacetonitrile; or a pharmaceutically acceptable salt form thereof.

[0193] In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of formulaIa or Ib or a pharmaceutically acceptable salt form thereof.

[0194] In another embodiment, the present invention provides a novelmethod for treating or preventing a disorder related to MEK, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of formula Ia or Ib or a pharmaceuticallyacceptable salt form thereof.

[0195] In another embodiment, the present invention provides novelcompounds of formula Ia or Ib or a pharmaceutically acceptable salt formthereof for use in therapy.

[0196] In another embodiment, the present invention provides novelcompounds of formula Ia or Ib or a pharmaceutically acceptable salt formthereof for the manufacture of a medicament for the treatment of aninflammatory disease.

[0197] In another embodiment, the present invention provides novelcompounds of formula Ia or Ib or a pharmaceutically acceptable salt formthereof for the manufacture of a medicament for the treatment of cancer.

[0198] In another embodiment, the present invention provides a novelmethod of treating a condition or disease wherein the disease orcondition is referred to as rheumatoid arthritis, osteoarthritis,periodontitis, gingivitis, corneal ulceration, solid tumor growth andtumor invasion by secondary metastases, neovascular glaucoma, multiplesclerosis, or psoriasis in a mammal, comprising: administering to themammal in need of such treatment a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt formthereof.

[0199] In another embodiment, the present invention provides a novelmethod of treating a condition or disease wherein the disease orcondition is referred to as fever, cardiovascular effects, hemorrhage,coagulation, cachexia, anorexia, alcoholism, acute phase response, acuteinfection, shock, graft versus host reaction, autoimmune disease or HIVinfection in a mammal comprising administering to the mammal in need ofsuch treatment a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt form thereof.

DEFINITIONS

[0200] The compounds herein described may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. Many geometric isomers of olefins, C=N double bonds,and the like can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. Cisand trans geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms. All chiral, diastereomeric, racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention.

[0201] “Substituted” is intended to indicate that one or more hydrogenson the atom indicated in the expression using “substituted” is replacedwith a selection from the indicated group(s), provided that theindicated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto(i.e., =O) group, then 2 hydrogens on the atom are replaced.

[0202] The present invention is intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0203] When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

[0204] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0205] As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. C₁₋₄ alkyl is intended to include C₁,C₂, C₃, and C₄ alkyl. Examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,and s-pentyl. “Alkoxy” represents an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.C₁₋₄ alkoxy is intended to include C₁, C₂, C₃, and C₄ alkoxy. Examplesof alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.

[0206] As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5 or 6 membered monocyclicaromatic ring which consists of carbon atoms and 1, 2, 3, or 4heterotams independently selected from the group consisting of N, NH, Oand S. It is to be noted that that the total number of S and O atoms inan aromatic heterocycle is not more than 1.

[0207] Examples of heterocycles include, but are not limited to,2H,6H-1,5,2-dithiazinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, pyrimidinyl, pyranyl,pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl,2H-pyrrolyl, pyrrolyl, tetrazolyl, 6H-1,2,5thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferredheterocycles include, but are not limited to, pyridinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, and imidazolyl.

[0208] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[0209] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,and nitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

[0210] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0211] “Prodrugs” are intended to include any covalently bonded carrierswhich release the active parent drug according to formula Ia or Ib invivo when such prodrug is administered to a mammalian subject. Prodrugsof a compound of formula Ia or Ib are prepared by modifying functionalgroups present in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula Ia or Ib wherein ahydroxy, amino, or sulfhydryl group is bonded to any group that, whenthe prodrug or compound of formula Ia or Ib is administered to amammalian subject, cleaves to form a free hydroxyl, free amino, or freesulfhydryl group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of alcohol andamine functional groups in the compounds of formula Ia or Ib.

[0212] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

[0213] “Therapeutically effective amount” is intended to include anamount of a compound of the present invention or an amount of thecombination of compounds claimed effective to inhibit MEK or treat thesymptoms of MEK over production in a host. The combination of compoundsis preferably a synergistic combination. Synergy, as described forexample by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurswhen the effect (in this case, MEK inhibition) of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased antiviral effect, or some other beneficialeffect of the combination compared with the individual components.

[0214] The term “radiosensitize”, as used herein refers to a processwhereby cells are made susceptible to radiation-induced cell death, orthe cells that result from the process.

SYNTHESIS

[0215] The compounds of the present invention can be prepared in anumber of ways known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or by variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

[0216] Compounds of the present invention (3) may be synthesized by theroute described in Scheme 1. A thiol 1, such as a thiophenol, may betreated with a malononitrile such as malononitrile 2 in the presence ofa base catalyst such as triethylamine, DBU, Hunig's base, or aqueousbase (for example, 10% NaOH), etc., in a nonreactive solvent such asTHF, acetone, etc., to yield the vinylogous cyanamide 3. The reactionmedium can be degassed to eliminate the presence of oxygen which canfacilitate disulfide formation via the dimerization of thiol 1. Thevinylogous cyanamide is frequently isolated as a mixture of Z- andE-isomers and the melting point varies significantly with isomercomposition. A crystalline single isomer or material enriched in oneisomer may sometimes be obtained by spontaneous crystallization of oneisomer, recrystallization, or stirring solid in a solvent whichdissolves only part of the material. Alternatively, isomers maysometimes be separated by chromatography. However, the double bond in 3isomerizes very easily. NMR spectroscopy of a single isomer in DMSO-d₆shows that an equilibrium mixture of Z- and E-isomers is generatedfaster than the spectrum could be obtained (about 5 minutes).Isomerization also takes place in other solvents such as water, acetone,methanol, and chloroform, but more slowly than in DMSO. Rapid NMR in oneof these solvents may be used to establish isomeric composition. For invitro assays, the compounds may be dissolved in DMSO to ensure that anequilibrium mixture of isomers is tested.

[0217] Many thiols (1) are commercially available. Alternatively, thereare many methods for their synthesis familiar to one skilled in the art.For example, aryl or heterocyclic anions may be quenched with sulfur toyield thiols (Chem. Pharm. Bull. 1989, 37 (1), 36). Displacement ofaryldiazonium salts with EtOCS₂K leads to aryl thiols (Collect. Czech.Chem. Commun. 1990, 55, 1266). The Newman rearrangement of phenols viatheir dimethylthiocarbamates leads to thiophenols (Organic Syntheses VI,(1988) 824).

[0218] When the Y group in Scheme 1 is substituted phenyl or naphthyl,the malononitrile precursors (2) to the compounds of this invention maybe prepared by one of the three routes shown in Scheme 2. In the firstroute, aryl iodides 4 may be treated with malononitrile in the presenceof a copper catalyst to yield arylmalononitriles 2 (J. Org. Chem. 1993(58) 7606-7). Malononitrile can also be coupled to aryl halides 4(X=halide) using (Ph₃P)₂PdCl₂ or Pd(Ph₃P)₄ in THF (J. Chem. Soc. Chem.Comm. 1984, 932-3). The aryl iodides needed for these methods arecommercially available or prepared by methods familiar to one skilled inthe art. In particular, aryl iodides may be prepared by iodination witha source of electrophilic iodine, such as iodine monochloride, or bydiazotization of anilines.

[0219] Arylmalononitriles may also be prepared from aryl acetonitrilesas shown the second route in Scheme 2. Aryl acetonitriles 5 may bedeprotonated with a base, such as LDA, and quenched with a electrophilicsource of cyanide, such as cyanogen chloride (J. Org. Chem. 1966, 21,919) or 2-chlorobenzylthiocyanate (J. Org. Chem. 1983, 48, 2774-5) toyield malononitrile 2. Along the same lines, acetonitrile 5 can also beacylated in the presence of NaOMe with dimethyl carbonate to form themethyl cyanoacetate (not shown in Scheme 2). Conversion of the methylester to a nitrile group via procedures familiar to one skilled in theart leads to malononitrile 2 (J. Am. Chem. Soc. 1904, 32, 119). The arylacetonitriles needed for these methods are commercially available orprepared by methods familiar to one skilled in the art, for example,from aryl acetamides or from toluenes. When R₂ is an optionallysubstituted phenoxy group, the initial step in the preparation of thecompounds of this invention may be an Ullmann condensation between anaryl halide and a phenol. (For useful protocols, see: U.S. Pat. No.4,288,386; and Tetrahedron (1961), 15, 144-153.) A methyl substituent oneither of these substrates may be subsequently converted to a —CH₂CNgroup by free radical halogenation, with a reagent such asN-bromosuccinimide, followed by displacement with cyanide.

[0220] As shown in the third route shown in Scheme 2, arylmalononitriles2 may also be synthesized from simpler bromo- or iodoarylmalononitriles.These bromo- or iodo-substituted arylmalononitriles may be prepared byeither of the first two routes indicated in Scheme 2 for the preparationof malononitriles. Bromo- or iodo-substituted arylmalononitriles undergohalogen-metal exchange in the presence of two or more equivalents of analkyllithium reagent, such as n-butyllithium, to form dianionintermediate 7. This process may be carried out in an ethereal solventsuch as THF at a temperature of −78 to 0° C. The dianion may be quenchedin situ with one equivalent of an electrophile, such as an aldehyde,alkyl halide, disulfide, ester, or ketone, to yield a substitutedmalononitrile 2 with a new R₂ group attached to the former site of thebromine or iodine atom. This is process is illustrated in more detail inScheme 3 for the case where Y is a 1,3-disubstituted phenyl group.3-Bromophenylmalononitrile (6) may be converted to dianion 7a

[0221] by deprotonation and halogen-metal exchange with 2 equivalents ofn-butyllithium in THF at −78° C. The dianion may be treated in situ withan aldehyde to produce hydroxy-phenylmalononitriles 8.Hydroxy-phenylmalononitriles 8 may be oxidized to the correspondingketo-phenylmalononitrile 9 using MnO₂ or a variety of other oxidizingagents familiar to one skilled in the art. Compounds 8 and 9 may bereduced to the corresponding CH₂R₂-substituted phenylmalononitriles 10using hydrogen and a noble metal catalyst, NaBH₄ and TFA (Synthesis1978, 763-5), or other procedures familiar to one skilled in the art.Malononitriles 8, 9, and 10 may be treated with thiols 1 to yield thecompounds of this invention. It must be noted that although only themetabromo isomer of 6 is pictured in Scheme 3, one trained in the artmay apply this methodology using other aryl halides and electrophiles toprepare isomers and compounds with different Y groups.

[0222] When Y is CHR₃, malononitrile precursors useful for preparationof the compounds of this invention have structure 2a and may be preparedas shown in Scheme 4. Knoevenagel condensation (Organic Reactions 15,204-509 15 (1967)) between an aldehyde 11 or a ketone 13 may be used toproduce alkylidene malononitriles 12 or 14. Conjugate addition of aGrignard or organolithium reagent to 12 affords the malononitrileprescursors 2 used in Scheme 1. Alternatively, alkylidene malononitriles14 may be 20 reduced to malononitriles 2a with sodium borohydride,catalytic hydrogenation or other reducing agents familiar to one skilledin the art. A third alternative is to alkylate malononitrile with analkyl halide 15 (X=halide).

[0223] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments which aregiven for illustration of the invention and are not intended to belimiting thereof.

EXAMPLES

[0224] Abbreviations used in the Examples are defined as follows: “1×”for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius,“eq” for equivalent or equivalents, “g” for gram or grams, “mg” formilligram or milligrams, “mL” for milliliter or milliliters, “¹H” forproton, “h” for hour or hours, “M” for molar, “min” for minute orminutes, “MHz” for megahertz, “MS” for mass spectroscopy, “NMR” fornuclear magnetic resonance spectroscopy, “rt” for room temperature,“tlc” for thin layer chromatography, “v/v” for volume to volume ratio.“α”, “β”, “R” and “S” are stereochemical designations familiar to thoseskilled in the art.

Example 1

[0225] Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile

[0226] Part A. Preparation of2-[(2-trifluoromethyl)phenyl]malononitrile.

[0227] A mixture of 2-trifluoromethyl-1-iodobenzene (21.76 g, 0.08 mol,1 eq), malononitrile (10.56 g, 0.16 mol, 2 eq), copper(I) iodide (1.52g, 0.008 mol, 0.1 eq), potassium carbonate (11.04 g, 0.32 mol, 4 eq),and 200 mL DMSO was stirred and heated at 120° C. for 21 h. The reactionmixture was cooled and poured into 1.2 L of 0.5 M HCl. The mixture wasfiltered and extracted with ethyl acetate. The organic layer was dried(MgSO₄) and the solvent removed in vacuo to yield an oil. This oil waspurified by flash chromatography on silica gel with 3:1 hexane/ethylacetate to yield 4.46 g (27%) of2-[(2-trifluoromethyl)phenyl]malononitrile as a yellow oil. ¹H-NMR(CDCl₃)δ: 8.05-7.10 (m, 4H); 5.30 (s, 1H).

[0228] Part B. Preparation ofα-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile.

[0229] 2-[(2-Trifluoromethyl)phenyl]malononitrile (the product from PartA) (3.07 g, 14.6 mmol, 1.1 eq), freshly distilled 4-aminothiophenol(1.66 g, 13.3 mmol, 1 eq), and THF (25 mL) were mixed. The reactionflask was then degassed by placing under vacuum followed by flushingwith N₂ several times to prevent disulfide formation.

[0230] After cooling to −78° C., triethylamine (1.85 mL, 13.3 mmol, 1eq) was added via syringe and the flask degassed once more. The contentswere allowed to warm to room temperature and the mixture was stirredovernight. TLC the following morning showed no malononitrile present,only thiol. Therefore, another 0.2 equivalents of malononitrile wereadded followed by degassing, followed by 0.5 equivalents oftriethylamine, followed by degassing. TLC after a few hours no startingmaterial was present. The reaction was worked up after stirring over theweekend at room temperature. The solvent was removed in vacuo and theresidue was purified by flash chromatography on silica gel with 25-100%ethyl acetate in hexane. Two fractions were isolated. The faster elutingfraction yielded 1.63 g of a tan oily solid. The slower eluting fractionyielded 2.61 g of a tan oily solid. Both compounds were recrystallizedfrom n-butylchloride. The faster eluting compound yielded 274 mg of awhite solid (m.p. 147.0-148.0° C.). This compound proved to be the Eisomer of the titled compound through NMR NOE experiments. The slowereluting compound yielded 1.85 g of a white solid (m.p. 130.0-130.5° C.).This compound proved to be the Z isomer of the titled compound throughNMR NOE experiments. Anal. calcd. for C₁₆H₁₂F₃N₃S (faster elutingisomer): C, 57.31; H, 3.62; F, 17.00; N, 12.53; S, 9.56. Found: C,57.19; H, 3.75; F, 16.83; N, 12.24; S, 9.50. Anal. calcd. forC₁₆H12F₃N₃S (slower eluting isomer): C, 57.31; H, 3.62; F, 17.00; N,12.53; S, 9.56. Found: C, 57.28; H, 3.80; F, 16.96; N, 12.37; S, 9.22.¹H-NMR (faster eluting isomer) (CDCl₃)δ 7.75 (d, 1H, J=7 Hz); 7.57 (t, 1H, J =7 Hz); 7.49 (t, 1H, J=7 Hz); 7.47 (d, 1H, J=7 Hz); 7.24 (d, 2H,J=7 Hz); 6.66 (d, 2H, J=7 Hz). ¹H-NMR (slower eluting isomer) (CDCl₃)δ7.75 (d, 1H, J=7 Hz); 7.58 (t, 1 H, J=7 Hz); 7.48 (t, 1H, J=7 Hz); 7.43(d, 1H, J=7 Hz); 7.40 (d, 2H, J=7 Hz); 6.68 (d, 2H, J=7 Hz).

Example 2

[0231] Z- andE-α-[amino[(2-aminophenyl)thiolmethylene]-3-(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile

[0232] Part A. Preparation of 2-(3-bromophenyl)malononitrile.

[0233] To a flame dried 5L 3-neck flask equipped with a mechamicaloverhead stirrer under nitrogen was added diisopropylamine (78.60 mL,0.56 mol, 2.2 eq) and 2 L of benzene. After cooling to 0-5° C., 1.6 Mn-BuLi (351.0 mL, 0.56 mol, 2.2 eq) was added dropwise via additionfunnel while keeping the temperature at 0-5° C. The LDA was stirred for45 min. at 0-5° C. 3-Bromophenylacetonitrile (50.0 g, 0.26 mol, 1.0 eq)dissolved in 200 mL of benzene was added dropwise via addition funnelkeeping the temperature at 0-5° C. The mixture was stirred an additional15 min at this temperature. 2-Chlorobenzylthiocyanate (J. Am. Chem.Soc., 1954, 76, 585) (103.0 g, 0.56 mol, 2.2 eq) dissolved in 200 mLbenzene was added dropwise via addition funnel keeping the temperatureat 0-5° C. During the addition, a precipitate formed. The reaction wasallowed to warm to room temperature and the mixture stirred overnight.The reaction was quenched by adding water and 200 mL 10% NaOH. Thelayers were separated, and the benzene layer extracted with 10% NaOH(3×1L). The basic layers were collected and acidified with conc. HCl topH 1-2. A precipitate formed. Methylene chloride was added to dissolvethe precipitate. The layers were separated and the aqueous layerreextracted with methylene chloride (2X). The methylene chloride layerswere collected, dried (MgSO₄) and the solvent removed in vacuo to yield65.32 g of 2-(3-bromophenyl)malononitrile as a yellow solid.Recrystallization from methylcyclohexane yielded two crops: crop 1,42.86 g of orange crystals, m.p. 99.5-101.5° C.; crop 2, 2.18 g oforange crystals, m.p. 97.0-99.0° C. Combined yield 79.9%. ¹H-NMR (CDCl₃)δ: 7.67 (s, 1H) ; 7.63 (d, 1H, J=7 Hz); 7.47 (d, 1H, J=7 Hz); 7.39 (t,1H, J=7 Hz); 5.08 (s, 1H).

[0234] Part B. Preparation of2-[3-[(4cyanophenyl)hydroxymethyl]phenyl]malononitrile

[0235] 2-(3-Bromophenyl)malononitrile (the product from part A) (1.00 g,4.52 mmol, 1 eq) was dissolved in dry THF (50 mL) under N₂ and cooled to−70° C. 1.6 M n-BuLi (5.94 mL, 9.50 mmol, 2.1 eq) was then addeddropwise via syringe maintaining the temperature at −65 to −70° C. Anorange slurry formed. The temperature was maintained for 20 min afterwhich 4-cyanobenzaldehyde (0.59 g, 4.52 mmol, 1 eq) was added viasyringe. After two hours, the reaction was complete. The reaction wasadded to water and the pH was adjusted to 3 with 1 N HCl. The mixturewas extracted with ethyl acetate (3X), the organic layers combined,dried (MgSO₄) and the solvent removed in vacuo to yield 1.84 g an anamber oil. Flash chromatography on silica gel with 7:3 to 1:1hexane/ethyl acetate yielded 2-(3-bromophenyl)malononitrile (0.88 g) asan amber oil. ¹H-NMR (CDCl₃) δ: 7.66 (d, 2H, J=7 Hz); 7.60-7.15 (m, 6H);5.95 (s, 1H); 5.07 (s, 1H); 2.63 (br s, 1H). NH₄-CI MS: 291 (M+NH₄)⁺.

[0236] Part C. Preparation of Z- andE-α-[amino[-(2-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzene-acetonitrile

[0237] 2-[3-[(4-Cyanophenyl)hydroxymethyl]phenyl]malononitrile (theproduct from part B) (250 mg, 0.915 mmol, 1 eq), 2-aminothiophenol (0.10mL, 0.915 mmol, 1 eq), triethylamine (0.13 mL, 0.915 mmol, 1 eq), andTHF were reacted by the procedure described in Example 1, part B. After4 hours, the solvent was then removed in vacuo and the residue purifiedby flash chromatography on silica gel with 1:1 hexane/ethyl acetate toyield the title compound (200 mg) as a mixture of isomers. HRMS calcd.for C₂₃H₁₈N₄OS: 399.1264; Found: 399.1280. ¹H-NMR (CDCl₃) δ: (majorisomer) 7.61 (d, 2H, J=7 Hz) ; 7.60-7.10 (m, 8H); 6.90-6.70 (m, 2H);5.86 (br s, 1H); 4.71 (br s, 2H); 4.44 (br s, 2H); 2.51 (br s, 1H).

Example 3

[0238] Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile

[0239] Part A. Preparation of2-[3-[(4-pyridyl)hydroxymethyl]phenyl]malononitrile

[0240] 2-(3-Bromophenyl)malononitrile (the product from Example 2, partA) (2.00 g, 9.05 mmol, 1 eq) was dissolved in dry THF (100 mL) under N₂and cooled to −70° C. 1.6 M n-BuLi (11.87 mL, 19.0 mmol, 2.1 eq) wasthen added dropwise via syringe maintaining the temperature at −65 to−70° C. An orange slurry formed. The temperature was maintained for 20min after which 4-pyridinecarboxaldehyde (0.86 mL, 9.05 mmol, 1 eq) wasadded via syringe. After one hour, the reaction was essentiallycomplete. It was worked up by adding water and adjusting the pH to 3with 1 N HCl. The mixture was extracted with ethyl acetate (3X), theorganic layers combined, dried (MgSO₄) and the solvent removed in vacuoto yield an an amber oil. Flash chromatography with 1:1 hexane/ethylacetate to 100% ethyl acetate yielded 0.95 g of an orange glass asproduct. ¹H-NMR (DMSO-d₆)δ: 8.41 (d, 2H, J=7 Hz); 7.26 (br s,1H);7.35-7.20 (m, 6H); 6.03 (br s, 1H); 5.65 (s, 1H).

[0241] Part B. Preparation ofα-[amino[(2-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile.

[0242] 2-[3-[(4-Pyridyl)hydroxymethyl]phenyl]malononitrile (the productfrom Part A) (850 mg, 3.41 mmol, 1 eq), 2-aminothiophenol (0.36 mL, 3.41mmol, 1 eq), triethylamine (0.48 mL, 3.41 mmol, 1 eq), and THF (20 mL)were reacted by the procedure described in Example 1, part B. As soon asthe triethylamine was added, a precipitate began to form. More THF wasadded (50 mL) but the precipitate did not dissolve. The mixture wasstirred overnight and the precipitate dissolved. TLC showed the reactionto be complete. The solvent was then removed in vacuo and the residuewas purified by flash chromatography on silica gel with 1:1 hexane/ethylacetate to 100% ethyl acetate to yield 950 mg of a white solid. Thesolid was stirred in THF and filtered to yield 462 mg of a white solid(mp 97.5-101.0° C.). NMR shows a mixture of isomers. An analyticalsample was prepared by recrystallization (50 mg) from ethyl acetate. Therecrystallized solids were filtered, rinsed with ether, and dried underhigh vacuum to yield 23 mg of a white solid (mp 150.0-151.0° C.). NMRshowed the presence of mainly one isomer. Anal calcd.for C₂₁H₁₈N₄OS·0.4H₂O: C, 66.09; H, 4.96; N, 14.68; S, 8.40. Found: C, 66.16; H, 5.03; N,14.46; S, 8.35. ¹H-NMR (major isomer) (acetone-d₆) δ 8.49 (d, 2H, J=7Hz); 7.52 (s, 1H); 7.50-7.20 (m, 7H); 7.00-6.80 (m, 1H); 6.70 (t, 1H,J=7 Hz); 5.84 (d, 1H, J=6 Hz); 5.80-5.50 (m, 2H); 5.45-5.30 (m, 2H);5.20 (d, 1H, J=6 Hz). The above procedure was repeated several times onlarger scale to yield 112.12 g of the title compound. This material wasstirred overnight at room temperature in 900 mL of ethyl acetate. Thesolids were filtered, rinsed with ether (1 L), and dried under highvacuum to yield 86.11 g of a white solid (mp 146.5-147.5° C.). Analcalcd.for C₂₁H₁₈N₄OS: C, 67.36; H, 4.86; N, 14.96; S, 8.56. Found: C,67.39; H, 4.94; N, 14.76; S, 8.84.

Example 4

[0243] Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-phenoxvbenzeneacetonitrile.

[0244] Part A. Preparation of 2,3-dimethyldiphenylether.

[0245]2,3-dimethylphenol (10 g, 82 mmol), sodium hydroxide (3.28 g, 82mmol), water (1.8 mL) and chlorobenzene (70 mL) were refluxed for 3 hunder nitrogen in a flask equipped with a Dean-Stark trap. Water andchlorobenzene removed from the trap several times (100 mL total) whileadding an equal volume of chlorobenzene to the flask. The resultingsuspension was dried further by refluxing through a soxhlet extractorfilled with 3A molecular sieves for 30 min. Cuprous iodide (0.81 g,0.082 mmol) and tris[2-(2-methoxyethoxy)ethyl]amine (1.5 mL, 4.1 mmol)were added and the reaction was refluxed overnight. The solution wasdecanted from the solid. Additional cuprous iodide (0.81 g, 0.082 mmol)and tris[2-(2-methoxyethoxy)ethyl]amine (1.5 mL, 4.1 mmol) were added tothe solution and the reaction was refluxed overnight with mechanicalstirring. The reaction mixture was absorbed onto silica gel and elutedwith hexane to afford the title compound (1.4 g). GC-MS: Calcd, 199;Found, 199. ¹H-NMR (CDCl₃)δ: 7.28 (t, 2H); 7.04 (m, 3H); 6.88 (d, 2H);6.78 (d, 1H); 2.32 (s, 3H); 2.25 (s, 3H).

[0246] Part B. Preparation of 2-(3-phenoxy-2-methylphenyl)malononitrile.

[0247] A solution of 2,3-dimethyldiphenylether (2.2 g, 11 mol),N-bromosuccinimide (1.76 g, 11 mmol) and benzoyl peroxide (0.27 g, 1mmol) in carbon tetrachloride (60 mL) was refluxed for 2.5 h. Thereaction mixture was added to methylene chloride and extracted withsaturated aqueous sodium bisulfite, water (twice), and brine. Theorganic layer was dried over sodium sulfate and the residue was purifiedby chromatography on silica gel with hexane to afford a mixture3-bromomethyl-2methyldiphenylether and2-bromomethyl-3methyldiphenylether (2.0 g).

[0248] A solution of the above bromination products (2.0 g, 7.2 mmol)and tetraethylammonium cyanide (1.2 g , 7.7 mmol) in dichloromethane (60mL) was refluxed for 1 h. The reaction was added to dichloromethane andextracted with 10% aqueous sodium hydroxide (three times) and brine(twice). After concentrating the organic layer, the residue was purifiedby chromatography on silica gel with toluene and 5% ethyl acetate intoluene to afford a 1:3 mixture of2-(3-phenoxy-2-methylphenyl)acetonitrile and2-(2-phenoxy-6-methylphenyl)acetonitrile (1.08 g). ¹H-NMR (CDCl₃) δ:6.7-7.2 (m, 8H) ; 3.78 (s, 1.5H) ; 3.74(s, 0.5H); 2.48 (s, 2.25H);2.28(s, 0.75H).

[0249] Methyllithium (4.3 mL of a 2.5 M solution, 10.7 mmol) was addedto a solution of diisopropylamine (1.5 mL, 10.7 mmole) in dry benzene(70 mL) cooled in an ice-water bath. After stirring for 1 h, a solutionof the above mixture of phenylacetonitriles in dry benzene (30 mL) wasadded dropwise. After stirring for 1 h at 0° C., a solution of2-chlorobenzylthiocyanate in dry benzene was added. After stirring for 1h while the reaction mixture warmed to room temperature, the reactionmixture was added to benzene and extracted with 10% aqueous sodiumhydroxide (4X). The combined aqueous layers were acidified to pH 1 withconcentrated hydrochloric acid and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate, concentrated, and purifiedtwice by silica gel chromatography with 0-10% ethyl acetate in tolueneand then 10% ether in hexane, removing the high Rf major isomer andaffording isomerically pure title compound (61 mg) as a pale yellowsolid. ¹NMR(CDCl₃) δ: 7.2-7.4 (m, 4H) ; 7.13 (t, 1H) ; 6.9-7.0 (m, 3H);5.10 (s, 1H); 2.40 (s, 3H). HRMS: Calculated for C₁₆H₁₂N₂O (M):248.0959; Found: 248.0950.

[0250] Part C. Preparation of Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-phenoxybenzeneacetonitrile.

[0251] A solution of 2-(3-phenoxy-2-methylphenyl)malononitrile (50 mg,0.20 mmol), 2-aminothiophenol (21 uL, 0.20 mmol) and triethylamine (28uL) in tetrahydrofuran was stirred under nitrogen overnight. Thereaction was added to water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated. The residue was purified by chromatography onsilica gel with 20-50% ether in hexanes to afford the title compound asa colorless oil (30 mg). ¹H-NMR (CDCl₃) was consistent with the presenceof a 1:1 mixture of isomers. δ: 7.49 (d, 0.5H); 6.7-7.4 (m, 11.5H); 4.83(br s, 1H); 4.51 (br s, 1H); 4.41 (br s, 1H); 4.33 (br s, 1H); 2.31 (s,1.5H); 2.25 (s, 1.5H). HRMS: Calculated for C₂₂H₂₀N₃OS (M+H): 374.1327;Found: 374.1307.

Example 5

[0252] Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-(2-methylphenyl)benzenepropanenitrile

[0253] Part A. Preparation of 2-(2-methylbenzylidene)malononitrile.

[0254] A solution of 2-methylbenzaldehyde (9.6 mL, 83 mmol),malononitrile (5.5 g, 83 mmol) and 3.5 M ammonium acetate in acetic acid(2.4 mL, 8.4 mmol) in isopropanol (83 mL) was stirred overnight at roomtemperature. A precipitate formed. Water (100 mL) was added and theprecipitate was collected. The precipitate was washed with water (50 mL)and vacuum dried to afford of 2-(2-methylbenzylidene)malononitrile (12.7g) as a white solid (mp 105-106°). ¹H-NMR (CDCl₃) δ: 8.10 (s 1H) ; 8.08(d, 1H); 7.50 (dd, 1H); 7.30-7.40 (m, 2H); 2,45 (s, 3H).

[0255] Part B. Preparation of2-[α-(2-methylphenyl)-4-chlorobenzyl]malononitrile.

[0256] 4-Chlorophenylmagnesium bromide (2.1 mL of a 1.0 M solution inether, 2.1 mmol) was added dropwise to a solution of2-(2-methylbenzylidene)malononitrile (0.32 g, 1.9 mmol) in drytetrahydrofuran (7.5 mL) at 0° C. and stirred for 1 h. Saturated aqueousammonium chloride was added and the layers were separated. The aqueouslayer was extracted twice with dichloromethane and the combined organicslayers were dried over magnesium sulfate. After concentrating, theresidue was purified by flash chromatography on silica gel with 12.5%ethyl acetate in hexanes to afford the title compound (0.25 g) as awhite solid (mp 132-140°). ¹H-NMR (CDCl₃):δ: 7.20-7.39 (m 8H); 4.78 (d,1H); 2.25 (s, 3H). GC-MS: m/e=281/283 (M+H).

[0257] Part C. Preparation of Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-(2-methylphenyl)benzenepropanenitrile.

[0258] A solution of 2-[α-(2-methylphenyl)-4-chlorobenzyl]malononitrile(0.20 g, 0.71 mmol), 2-aminothiophenol (0.11 mL, 1.00 mmol) andtriethylamine (0.14 mL, 1.00 mmol) in tetrahydrofuran (1.4 mL) wasstirred under nitrogen for 78 h. The reaction mixture was absorbed ontosilica gel and eluted with 20-30% ethyl acetate in hexanes to afford thetitle compound (253 mg) as a white foam (mp 63.5-72°). ¹H-NMR (CDCl₃)was consistent with the presence of a 4:6 mixture of isomers: δ 7.44 (d,0.4H); 7.10-7.36 (m, 9.6H); 6.71-6.79 (m, 2H); 5.34 (s, 0.6H); 4.97 (s,0.4H); 4.65 (br s, 1.2H); 4.44 (br s, 0.8H); 4.12 (br s, 2H); 2.33 (s,1.8H); 2.22 (s, 1.2H). HRMS: Calcd for C₂₃H₂₁N₃SCl (M+H), 406.1145;Found, 406.1130. Elem. Anal. Calcd for C₂₃H₂₀N₃SCl: C, 68.05, H, 4.98;N, 10.35; S, 7.91.Found: C, 68.03, H, 5.09; N, 10.20; S, 7.97.

Examples 6-51

[0259] The following compounds were prepared by procedures similar tothose described above. Ex. Name 6 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-β-phenylbenzenepropanenitrile 7 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile 8 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile 9 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile 10 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile 11 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile 12 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile 13 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile 14 Z- andE-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile 15 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile 16 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile 17 Z- andE-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile 18 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile 19 Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile 20 Z- andE-α-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile 21 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile 22 Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile 23 Z- andE-α-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile 24 Z- andE-α-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile 25 Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-2- bromobenzeneacetonitrile 26Z- and E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile 27 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile 28 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile 29 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-phenylbenzenepropanenitrile 30 Z- andE-α-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile 31 Z- andE-α-[amino[(2,4-diaminophenyl)thio]methylene]-1- naphthyleneacetonitrile32 Z- and E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-β-(4-pyridyl)benzenepropanenitrile 33 Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-3- (benzyl)benzeneacetonitrile34 Z- and E-α-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile 35 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile 36 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-β-(1-methyl-2-pyrrolyl)benzenepropanenitrile 37 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3- phenoxybenzeneacetonitrile38 Z- and E-α-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile 39 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile 40 Z- andE-α-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile 41 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile 42 Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-2- methylbenzeneacetonitrile43 Z- and E-α-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile 44 Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-1- naphthyleneacetonitrile 45Z- and E-α-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile 46 Z- andE-α-[amino[(2-aminophenyl)thio]methylene]-1- naphthyleneacetonitrile 47Z- and E-α-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile 48 Z- andE-α-[amino[(4-aminophenyl)thio]methylene]-4- methylbenzeneacetonitrile49 Z- and E-α-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile 50 Z- andE-α-[amino[(2-fluorophenyl)thio]methylene]-1- naphthyleneacetonitrile 51Z- and E-α-[amino[(2-aminophenyl)thio]methylene]-3-phenylbenzeneacetonitrile

[0260] HRMS HRMS Example FORMULA Calculated* Found* 6 C23H20ClN3S406.1145 406.1148 7 C22H17N5O5S 464.1029 464.1024 8 C24H21N3O3S 432.1382432.1364 9 C22H18N4O3S 419.1178 419.1168 10 C22H14F5N3OS 464.0856464.0827 11 C22H20N4OS 389.1436 389.1428 12 C23H21N3OS 388.1484 388.147113 C22H20N4OS 388.1436 388.1436 14 C23H17N3O2S 400.1120 400.1105 15C22H18N4O3S 419.1179 419.1156 16 C23H16F5N3OS 478.1013 478.1002 17C21H18N4OS 376.1120 376.1103 18 C23H18F3N3OS 442.1201 442.1200 19C21H18N4OS 375.1280 375.1268 20 C21H17N3OS 376.1120 376.1104 21C23H18N4OS 399.1280 399.1273 22 C23H18N4OS 399.1280 399.1265 24C21H17N3OS 360.1171 360.1172 25 C15H12BrN3S 360.1171 360.1172 26C24H23N3OS 402.1640 402.1648 27 C22H19N3OS 374.1327 374.1327 28C20H17N3OS2 379.0813 (M+) 379.0799 (M+) 29 C22H18ClN3S 392.0988 392.098230 C20H16N2OS2 365.0782 365.0763 31 C19H16N4S 333.1174 333.1166 32C22H20N4S 373.1496 373.1487 33 C22H19N3S 358.1378 358.1393 34 C23H17N3S368.1221 368.1227 35 C22H17N3OS 372.1171 372.1160 36 C21H20N4S 361.1487361.1479 37 C21H17N3OS 360.1171 360.1144 39 C20H17N3O2S 364.1120364.1097 40 C20H11F5N2OS2 455.0311 455.0305 41 C22H20N4OS 389.1436389.1431 43 C19H21N3S 324.1534 324.1524 44 C19H15N3S 318.1065 318.107645 C16H12F3N3S 336.0782 336.0782 46 C19H15N3S 318.7065 318.1048 47C16H12F3N3S 336.0782 336.0776 51 C21H17N3S 344.1221 334.1208

[0261] Example Solvent Chemical Shift 23 CDCl3 7.15-7.65 (m, 13H); 5.85& 2.88 (2 d, 1H); 4.61 & 4.88 (2 br s, 2H); 2.50 & 2.59 (2 d, 2H). 25CDCl3 6.64-7.68 (m, 8H); 3.95-4.81 (3 br s, 4H). 38 CDCl3 6.54-7.71 (m,8H); 4.37-4.90 (4 br s, 4H). 42 CDCl3 6.56-7.43 (m, 8H); 3.75-4.70 (4 brs; 4H); 2.37 & 2.40 (2 s, 3H). 48 CDCl3 6.57-7.41 (m, 8H); 3.75-4.74 (4br s, 4H); 2.33 & 2.34 (2 s, 3H). 49 CDCl3 6.72-7.54 (m, 8H); 4.26-4.80(3 br s, 4H); 2.36 & 2.43 (2 s, 3H).

UTILITY

[0262] Compounds of the present invention are inhibitors of thedual-specificity kinase MEK1/MEK2 (Mapk or Erk kinase, whereMapk=mitogen-activated protein kinase) and are expected to be useful fortreating proliferative diseases, e.g. cancer, psoriasis, restenosis oratherosclerosis, and also autoimmune diseases. The presently claimed MEKinhibitors are also expected to have utility as radiosensitizers for thetreatment of solid tumors. In addition, the presently claimed compoundsare expected to have utility for the treatment of chronic pain or forinhibiting memory acquisition. Assays for chronic pain are found Scienceand Medicine (1996), Nov./Dec., 22-31. Assays for mammalian associativelearning are found in Nature Neuroscience (1998) 1 (1) 602-609.

[0263] The ERK signal transduction pathway includes two very similarforms of MEK, MEK1 and MEK2, and two similar forms of ERK, ERK1 andERK2. To block signal transduction via the ERK pathway, a MEK inhibitormust prevent ERK1 and/or ERK2 from being phosphorylated (and therebyactivated) by the kinases MEK1 or MEK2. The different roles played byMEK1 and MEK2 and by ERK1 and ERK2 are not currently understood wellunderstood and they may be redundant under some or all circumstances.MEK1 and MEK2 are phosphorylated (and thereby activated) by an upstreamkinase, RAF. Since MEK1 or MEK2 have little ability to phosphorylateERK1 and ERK2 until they have been phosphorylated and since they areusually isolated in their unphosphorylated state, it is difficult toobtain adequate quantities of phosphorylated MEK1 or MEK2 suitable forassaying many compounds. To make assays more practical, a constitutivelyactive mutant of MEK1 (e.g., 2×-MEK1)(see J. Biol. Chem. (1998) 29,18623-18632) was initially used to characterize the MEK inhibitors ofthis invention. This mutant enzyme has negatively-charged residues atthe residues which are normally phosphorylated by RAF. Selectedinhibitors of 2×-MEK1 disclosed herein have been shown to be inhibitorsof phosphorylated (i.e., active) wild-type MEK1 and MEK2. Furthermore,many of the MEK inhibitors of this invention have been shown to becapable of blocking phosphorylation of ERK induced by treatment ofJurkat cells with TPA (see J. Biol. Chem. (1998) 29, 18623-18632).

[0264] Selected MEK inhibitors from this invention have also been shownto block the upregulation of AP-1 expression in Cos-7 cells induced bystimulation with TPA (see J. Biol. Chem. (1998) 29, 18623-18632). AP-1in turn regulates the expression of a number of pro-inflammatory andgrowth-stimulating genes including. These experiments prove thatinhibitors of 2×-MEK1 function as inhibitors of MEK and ERK signaltransduction in cell culture.

DOSAGE AND FORMULATION

[0265] The compounds of this invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions: They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

[0266] The dosage regimen for the compounds of the present inventionwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. A physician or veterinarian candetermine and prescribe the effective amount of the drug required toprevent, counter, or arrest the progress of the thromboembolic disorder.

[0267] By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

[0268] Compounds of this invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using transdermal skin patches. When administered in the form ofa transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen.

[0269] The compounds are typically administered in admixture withsuitable pharmaceutical diluents, excipients, or carriers (collectivelyreferred to herein as pharmaceutical carriers) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, and syrups, and consistent with conventionalpharmaceutical practices.

[0270] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, and sorbitol; for oraladministration in liquid form, the oral drug components can be combinedwith any oral, non-toxic, pharmaceutically acceptable inert carrier suchas ethanol, glycerol, and water. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents, and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, andsodium chloride. Disintegrators include, without limitation, starch,methyl cellulose, agar, bentonite, and xanthan gum.

[0271] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[0272] Compounds of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[0273] Dosage forms (pharmaceutical compositions) suitable foradministration may contain from about 1 milligram to about 100milligrams of active ingredient per dosage unit. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-95% by weight based on the total weight of thecomposition.

[0274] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, and stearic acid. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

[0275] Liquid dosage forms for oral administration can contain coloringand flavoring to increase patient acceptance.

[0276] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

[0277] Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

[0278] Representative useful pharmaceutical dosage-forms foradministration of the compounds of this invention can be illustrated asfollows:

Capsules

[0279] A large number of unit capsules can be prepared by fillingstandard two-piece hard gelatin capsules each with 100 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

[0280] A mixture of active ingredient in a digestable oil such assoybean oil, cottonseed oil or olive oil may be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules should be washed and dried.

Tablets

[0281] Tablets may be prepared by conventional procedures so that thedosage unit is 100 milligrams of active ingredient, 0.2 milligrams ofcolloidal silicon dioxide, 5 milligrams of magnesium stearate, 275milligrams of microcrystalline cellulose, 11 milligrams of starch and98.8 milligrams of lactose. Appropriate coatings may be applied toincrease palatability or delay absorption.

Injectable

[0282] A parenteral composition suitable for administration by injectionmay be prepared by stirring 1.5% by weight of active ingredient in 10%by volume propylene glycol and water. The solution should be madeisotonic with sodium chloride and sterilized.

Suspension

[0283] An aqueous suspension can be prepared for oral administration sothat each 5 mL contain 100 mg of finely divided active ingredient, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

[0284] Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

[0285] Where the compounds of Formula I are administered in combinationwith an anti-platelet agent, by way of general guidance, typically adaily dosage may be about 0.01 to 25 milligrams of the compound ofFormula I and about 50 to 150 milligrams of the anti-platelet agent,preferably about 0.1 to 1 milligrams of the compound of Formula I andabout 1 to 3 milligrams of antiplatelet agents, per kilogram of patientbody weight.

[0286] Where the compounds of Formula I are adminstered in combinationwith thrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

[0287] Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

[0288] Particularly when provided as a single dosage unit, the potentialexists for a chemical interaction between the combined activeingredients. For this reason, when the compound of Formula I and asecond therapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

[0289] These as well as other ways of minimizing contact between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time by the same manner, will be readily apparent tothose skilled in the art, once armed with the present disclosure.

[0290] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed is:
 1. A compound of formula Ia or Ib:

or stereoisomer or pharmaceutically acceptable salt form thereof,wherein; R¹ is phenyl, naphthyl, 2,3-dihydroindol-5-yl or a 5-6 memberedheteroaryl ring with 1-4 heteroatoms selected from N, NH, O, and S, andR¹ is substituted with 0-2 R^(a); R^(a) is selected from H, Cl, F, Br,I, C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, CH₂OH, NH₂, (C₁₋₃ alkyl)NH, (C₁₋₃alkyl)₂N, (H₂NCH₂C(O))NH, (H₂NCH(CH₃)C(O))NH, (CH₃NHCH₂C(O))NH,((CH₃)₂NCH₂C(O))NH, CF₃, OCF₃, CN, NO₂, C(O)NH₂, and CH₃C(O)NH; Y isselected from phenyl substituted with 0-5 R^(b), naphthyl substitutedwith 0-5 R^(b), and CHR³; R^(b) is selected from H, Cl, F, Br, I, C₁₋₄alkyl, OH, C₁₋₄ alkoxy, CH₂OH, CH(OH)CH₃, CF₃, OCF₃, —CN, NO₂, NH₂,(C₁₋₃ alkyl)NH, (C₁₋₃ alkyl)₂N, and C(O)O—C₁₋₄ alkoxy; R² is selectedfrom H, R^(2a), C(O)R^(2a), CH(OH)R^(2a), CH₂R^(2a), OR^(2a), SR^(2a),and NHR^(2a); R^(2a) is selected from phenyl, naphthyl, and a 5-6membered heteroaryl ring with 1-4 heteroatoms selected from N, NH, O,and S, and R^(2a) is substituted with 0-5 R^(b); R³ is phenylsubstituted with 0-2 R^(c) or naphthyl substituted with 0-2 R^(c); and,R^(c) is selected from H, Cl, F, Br, I, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,CH₂OH, CH(OH)CH₃, CF₃, OCF₃, —CN, NO₂, NH₂, (C₁₋₃ alkyl)NH, (C₁₋₃alkyl)₂N, and C(O)O-C₁₋₄ alkoxy.
 2. A compound of claim 1, wherein: R¹is phenyl or a 5-6 membered heteroaryl ring with 1-2 heteroatomsselected from N, NH, O, and S, and R¹ is substituted with 0-2 Ra; R^(a)is selected from H, Cl, F, C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, CH₂OH, NH₂,(C₁₋₃ alkyl)NH, (C₁₋₃ alkyl)₂N, (H₂NCH₂C(O))NH, (H₂NCH(CH₃)C(O))NH,(CH₃NHCH₂C(O))NH, ((CH₃)₂NCH₂C(O))NH, and CH₃C(O)NH; Y is selected fromphenyl substituted with 0-5 R^(b), naphthyl substituted with 0-5 R^(b),and CHR³; R^(b) is selected from H, Cl, F, Br, C₁₋₄ alkyl, OH, C₁₋₄alkoxy, CH₂OH, CH(OH)CH₃, CF₃, —CN, NO₂, NH₂, and (C₁₋₃ alkyl)NH, (C₁₋₃alkyl)₂N; R² is selected from H, R^(2a), C(O)R^(2a), CH(OH)R^(2a),CH₂R^(2a), and OR^(2a); R^(2a) is selected from phenyl, naphthyl, and a5-6 membered heteroaryl ring with 1-4 heteroatoms selected from N, NH,O, and S, and R^(2a) is substituted with 0-5 R^(b); R³ is phenylsubstituted with 0-2 R^(c) or naphthyl substituted with 0-2 R^(c); and,R^(c) is selected from H, Cl, F, Br, I, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,CH₂OH, CH(OH)CH₃, CF₃, —CN, NO₂, NH₂, (C₁₋₃ alkyl)NH, and (C₁₋₃alkyl)₂N.
 3. A compound according to claim 2, wherein: R¹ is phenyl or a5-6 membered heteroaryl ring with 1-2 heteroatoms selected from N, NH,O, and S, and R¹ is substituted with 0-2 R^(a); R^(a) is selected fromH, OH, and NH₂; Y is selected from phenyl substituted with 0-2 R^(b),naphthyl substituted with 0-2 R^(b), and CHR³; R^(b) is selected from H,Cl, F, Br, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CH₂OH, CH(OH)CH₃, CF₃, —CN, NO₂,NH₂, and (C₁₋₃ alkyl)NH, (C₁₋₃ alkyl)₂N; R² is selected from H, R^(2a),C(O)R^(2a), CH(OH)R^(2a), CH₂R^(2a), and OR^(2a); R^(2a) is selectedfrom phenyl, naphthyl, and a 5-6 membered heteroaryl ring with 1-4heteroatoms selected from N, NH, O, and S, and R^(2a) is substitutedwith 0-5 R^(b); R³ is phenyl substituted with 0-2 R^(c) or naphthylsubstituted with 0-2 R^(c); and, R^(c) is selected from H, Cl, F, Br, I,C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CH₂OH, CH(OH)CH_(3,) CF₃, —CN, NO₂, NH₂,(C₁₋₃ alkyl)NH, and (C₁₋₃ alkyl)₂N.
 4. A compound according to claim 1,wherein the compound is selected from: E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-β-phenylbenzenepropanenitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrileE- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-;yridyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[4-pyridyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3nitrophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile; E-andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-phenylbenzenepropanenitrile;E- andZ-α-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-β-(4-pyridyl)benzenepropanenitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-3-(benzyl)benzeneacetonitrile;E- and Z-α-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-β-(1-methyl-2-pyrrolyl)benzenepropanenitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile; E-andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;E- andz-α-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile; E-andZ-α-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile; E-andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;E- andZ-α-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;E- andZ-α-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;E- andZ-α-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile;and, E- and Z-α-[amino[(2-aminophenyl)thio]methylene]-3-phenylbenzeneacetonitrile; or a pharmaceutically acceptable salt form thereof.5. A compound according to claim 1, wherein the compound is selectedfrom:E-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-β-phenylbenzenepropanenitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-phenylbenzenepropanenitrile;E-α-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-β-(4-pyridyl)benzenepropanenitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-3-(benzyl)benzeneacetonitrile;E-α-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-β-(1-methyl-2-pyrrolyl)benzenepropanenitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;E-α-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;E-α-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;E-α-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile;and, E-α-[amino[(2-aminophenyl)thio]methylene]-3-phenylbenzeneacetonitrile; or a pharmaceutically acceptable salt form thereof.6. A compound according to claim 1, wherein the compound is selectedfrom:Z-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-2-methyl-β-phenylbenzenepropanenitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dinitrophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-carbomethoxyphenyl)hydroxymethyl]benzeneacetonitrileZ-α-[amino[(2-aminophenyl)thio]methylene]-3-[(4-nitrophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-nitrophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-3-[(pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-trifluoromethylphenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(4-hydroxyphenyl)thio]methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-cyanophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino(phenylthio)methylene]-3-[(4-cyanophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino(phenylthio)methylene]-3-[(4-pyridyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2,4-dimethylphenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-thienyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-4-chloro-β-phenylbenzenepropanenitrile;Z-α-[amino[(2-thienyl)thio]methylene]-3-[(phenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2,4-diaminophenyl)thio]methylene]-1-naphthyleneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methyl-β-(4-pyridyl)benzenepropanenitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]3-(benzyl)benzeneacetonitrile;Z-α-[amino[(2-naphthyl)thio]methylene]-1-naphthyleneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-(benzoyl)benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-β-(1-methyl-2-pyrrolyl)benzenepropanenitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-phenoxybenzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-bromobenzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(2-furanyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-thienyl)thio]methylene]-3-[(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-3-[(3-methyl-2-pyridyl)hydroxymethyl]benzeneacetonitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]-4-(1,1-dimethylethyl)benzeneacetonitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;.Z-α-[amino[(2-aminophenyl)thio]methylene]-3-(trifluoromethyl)benzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-1-naphthyleneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile;Z-α-[amino[(4-aminophenyl)thio]methylene]-4-methylbenzeneacetonitrile;Z-α-[amino[(2-aminophenyl)thio]methylene]-2-methylbenzeneacetonitrile;Z-α-[amino[(2-fluorophenyl)thio]methylene]-1-naphthyleneacetonitrile;and, Z-α-[amino[(2-aminophenyl)thio]methylene]-3-phenylbenzeneacetonitrile; or a pharmaceutically acceptable salt form thereof.7. A pharmaceutical composition, comprising: a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt form thereof.
 8. Amethod for treating or preventing a disorder related to MEK, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltform thereof.
 9. A method of treating a condition or disease wherein thedisease or condition is referred to as theumatoid arthritis,osteoarthritis, periodontitis, gingivitis, corneal ulceration, solidtumor growth and tumor invasion by secondary metastases, neovascularglaucoma, multiple sclerosis, or psoriasis in a mammal, comprising:administering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt form thereof.
 10. A method of treating a condition ordisease wherein the disease or condition is referred to as fever,cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia,alcoholism, acute phase response, acute infection, shock, graft versushost reaction, autoimmune disease or HIV infection in a mammalcomprising administering to the mammal in need of such treatment atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof.